Comparison of Lipid Amphotericin B Preparations in Treating Murine Zygomycosis

Abstract

We compared the efficacies of liposomal amphotericin B (LAmB) and an amphotericin B lipid complex (ABLC) in diabetic ketoacidotic (DKA) or neutropenic mice with disseminated zygomycosis. ABLC was as effective as LAmB in neutropenic but not DKA mice. Low-dose ABLC was less effective than LAmB at reducing brain fungal burdens in both models.Case reports and case series have documented successful outcomes after the treatment of zygomycosis with either liposomal amphotericin B (LAmB) or an amphotericin B lipid complex (ABLC) (1,4,14,15). To date, there have been no head-to-head preclinical or clinical studies comparing the efficacy of LAmB to that of ABLC for zygomycosis. However, relevant to the treatment of central nervous system (CNS) zygomycosis, a previous rabbit study demonstrated that LAmB penetrates the brain parenchyma at levels more than fivefold above those of ABLC (6). In fact, in that study, the levels of ABLC in the brain were less than or equal to the levels of amphotericin B deoxycholate, despite the fact that ABLC was administered at a fivefold-higher dose. Conversely, recent data demonstrated the efficacy of ABLC therapy in treating experimental CNS aspergillosis (3) and rabbit coccidioidal meningitis (2), suggesting the ability of ABLC to penetrate the brainblood barrier. A recent retrospective review of 120 cases of zygomycosis in patients with hematological malignancies demonstrated that treatment with LAmB was associated with a 67% survival rate, compared to a 39% survival rate when patients were treated with amphotericin B deoxycholate (P ϭ 0.02; 2 test) (5). No comparable data set from a review of the effect of ABLC in this setting has been published. Therefore, we sought to compare the efficacy of LAmB to that of ABLC in treating zygomycosis.(This work was presented in part at the 47th Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, IL, 17 to 20 September 2007 [12].)To define the relative efficacies of ABLC and LAmB against zygomycosis, we utilized our diabetic ketoacidotic (DKA) mouse model of disseminated zygomycosis, in which heavy infection occurs both systemically and specifically in the CNS (7-10). BALB/c male mice (20 to 23 g) were rendered diabetic with a single intraperitoneal injection of 210 mg of streptozotocin/kg of body weight in 0.2 ml of citrate buffer 10 days prior to fungal challenge, as we have previously described (7-10). Glycosuria and ketonuria were confirmed in all mice 7 to 10 days after streptozotocin treatment. Diabetic mice were infected via the tail vein with Rhizopus oryzae 99-880, a clinical brain isolate known to be virulent and tropic toward the brain in our model and susceptible to amphotericin B (MIC ϭ 0.25 g/ml) (8). LAmB or ABLC (7.5 or 15 mg/kg/day) was diluted in 5% dextrose water and administered intravenously (i.v.) in 0.2 ml for 4 days starting 24 h after infection. These doses were selected based on results from prior studies demonstrating

Comparative Pharmacodynamics of Amphotericin B Lipid Complex and Liposomal Amphotericin B in a Murine Model of Pulmonary Mucormycosis

“…The authors' findings of improved survival with L-AMB treatment compared with that with ABLC treatment is not surprising, given the method of infection (intravenous injection) and the tissue sites that would favor the formulation with higher sustained bloodstream concentrations, i.e., L-AMB. When the findings of those studies are compared with our data, these studies underscore how differences in the efficacies of lipid AMB formulations cannot be extrapolated to all infection sites and immunosuppression backgrounds (11).…”

“…Ibrahim and colleagues utilized diabetic ketoacidotic (DKA) and neutropenic murine models to compare the activities of L-AMB and ABLC against disseminated mucormycosis (11). In the DKA model, treatment with ABLC at 7.5 or 15 mg/kg/day was associated with a significantly poorer rate of survival compared to that achieved with a similar L-AMB treatment dose.…”

Diagnosis and treatment of mucormycosis in patients with hematological malignancies: guidelines from the 3rd European Conference on Infections in Leukemia (ECIL 3)

“…60 The same investigators compared the efficacies of L-AmB and ABLC in diabetic ketoacidotic, as well as neutropenic mice, with disseminated mucormycosis, and found that ABLC was as effective as L-AmB in neutropenic but not ketoacidotic mice. In addition, low-dose ABLC was less effective than L-AmB at reducing brain fungal burdens in both models, 61 and the superior GDF penetration of L-AmB in the CNS compared to ABLC has been shown in a rabbit model of Candida meningoencephalitis. 62 Different findings were reported in another study in which the pharmacodynamics of ABLC and L-AmB were compared in a murine model of pulmonary mucormycosis.…”

A pharmacoeconomic evaluation of capsofungin and amphotericin B for intravenous infusion for treatment of systemic fungal infection

“…Studija je pokazala da kaspofungin izaziva znatno manje nefrotoksičnosti (2,6%) i drugih neželjenih reakcija (5%) nego LAmB (11,5% i 8%, respektivno). Pošto u Srbiji L-AmB nije dostupan, troškovi su uzeti za ABLC, jer je efikasnost ova dva oblika ista (10)(11)(12), a pretragom literature nije pronađena nijedna studija koja bi poredila kaspofungin i ABLC. U studiji koja je poredila bezbednost L-AmB i ABLC u empirijskoj terapiji febrilne neutropenije, LAmB je pokazao značajno manju učestalost groznice, drhtavice, kao i nefrotoksičnosti u odnosu na ABLC (13).…”